tbuckley/cabot-search huggingface dataset:
Abstract 13991: Acute Procedural and Clinical Outcome Comparison Using the First and Second-Generation Cryoballoon: Inside a Large Cohort of Data Derived From Real World Multicentric Experience
Authors: Luigi Padeletti, Giuseppe Arena, Claudio Tondo, Stefano Fumagalli, Maurizio Lunati, Stefano Porcellini, Domenico Catanzariti, Luigi Sciarra, Loira Leoni, Gaetano Senatore, Antonio Curnis
Journal: Circulation (2015)

Introduction: Limited data are available on safety and efficacy of second-generation cryoballoon (CB2) for cryoablation of atrial fibrillation (CBA). Hypothesis: To evaluate in a large cohort of patients treated in real world clinical settings, demographics, procedural data and outcomes comparing CB2 to first-generation cryoballoon (CB1). Methods: Between 2012 and 2014, 581 patients (74% men, 59±10 years, 78% paroxysmal AF, LA diameter: 41±6 mm) suffering from AF and undergoing pulmonary veins (PV) CBA were prospectively enrolled in ClinicalService® framework One Shot TO Pulmonary vein isolation (1STOP) project. The cohort was divided into 2 groups according to the cryoballoon used in standard clinical practice: 120 (21%) CB1 and 461 (79%) CB2. Results: Clinical and demographic characteristics were similar in the two cohorts; procedure, fluoroscopy and ablation time were significantly lower in CB2 respect to CB1 (141±40 vs 166±50 min, p&lt;.001; 35±15 vs 41±15 min, p&lt;.001; 27±17 vs 41±26 min, p&lt;.001) with comparable acute success rate (97.8 vs 97.4%, p=ns); 22 patients (3.8%) experienced procedural complications. The most frequent acute procedural complication was transient diaphragmatic paralysis, significantly lower in CB2 vs CB1 (0.7 vs 3.3%, p=.016). Data at a minimum FU of 6 months were available for 237 (41%) patients: annual rate of follow-up complications was significantly lower in CB2 vs CB1 (Rate*100 pt/years: 5.74 vs 17.92, Incidence Rate Ratio - IRR: 0.32; 95% CI 0.17- 0.60; p&lt;.001) as well as CB2 was associated with lower PV reconnection rate causing redo ablation (Rate*100 pt/years: 0.64 vs 4.98; IRR: 0.13; 95% CI 0.05-0.30; p&lt;.001); 25 complications in 16 patients have been reported during FU, 21 (84%) of which for AF recurrence. Kaplain Meier analysis showed that freedom from AF at 12 months for patients with paroxysmal indication, considering a blanking period of 3 months, was 67.8% (95% CI 53.1-78.8%) in CB1 group and 77.8% (95% CI 68.6-84.7%) in CB2. Conclusions: The novel cryoballoon Arctic Front Advance (CB2) has proven to achieve, in a large clinical standard setting, significantly faster CBA times in comparison with the first-generation balloon, results also in lower acute procedural complication rates and a 78% 1-year freedom from AF.
Abstract 11563: Proteomic Analysis of Adult Congenital Heart Disease Associated Pulmonary Hypertension
Authors: Li Li, Changming Xiong, Enci Hu, Shian Huang, Chao Liu, Hongyue Wang, Xuejing Duan, Ranxu Zhao, Jianguo He
Journal: Circulation (2015)

Introduction: Pulmonary arterial hypertension (PAH) is a relative common complication in patients with congenital heart disease (CHD), affecting both disease progression and prognosis. The pathogenic mechanisms that lead to “irreversible” PAH are therefore poorly understood in subjects with CHD. Hypothesis: The aim of this study was to apply proteomics to discover protein regulations in the lungs of irreversible PAH patients, which could lead to generation of new hypotheses concerning signaling pathways and elucidating the pathophysiology of irreversible PAH. Methods: Label-free liquid chromatography tandem mass spectrometry was used to compare protein profiles in surgical samples of lungs from 4 patients with irreversible CHD-PAH, 4 reversible CHD-PAH and 4 control subjects. Result: A total of 133 proteins were differently expressed. The majority of differential expressed proteins were associated with cytoskeleton remodeling, integrin-mediated cell adhesion and migration, endothelial cell contacts, blood coagulation and HDL-mediated reverse cholesterol transport. Novel findings included increased expression of filamin A and caveolin-1 and decreased expression of glutathione S-transferase (GST) family. Filamin A, a major isoform of the filamin family which is a family of cytoskeletal proteins that have been implicated as critical mediators of organ development and cell signaling and migration. In the present study, the density and cellular location of filamin A immunoreactivity was accordant with caveolin-1. The results were confirmed by Western blot and immunohistochemistry. In reversible CHD-PAH and control lung tissue, filamin A and caveolin-1 were prominent in endothelium of pulmonary arteriole. In irreversible CHD-PAH lung tissue, they were prominent in the vascular smooth muscle cell. Conclusions: Label-free proteomics identified differences in the expression of several proteins in the CHD-PAH lung, many of which are relevant to the cell proliferation, differentiation and migration. Increased expression of filamin A and caveolin-1 may be pertinent to the proliferation and migration of vascular smooth muscle cell. Decreased expression of GST indicated impaired anti-oxidative function in irreversible CHD-PAH.
Abstract 12350: Pressure-flow Relationship of Pulmonary Circulation Determines Six-minute Walk Distance in Connective Tissue Disease
Authors: Kenya Kusunose, Hirotsugu Yamada, Mika Bando, Susumu Nishio, Yukina Hirata, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata
Journal: Circulation (2015)

Introduction: The 6-minute walk distance (6MWD) as a surrogate of exercise capacity is often shown to be the best predictor of mortality in pulmonary hypertension (PH). Recent studies have described that mean pulmonary artery pressure (mPAP) - cardiac output (CO) relationships have a potential to assess the detail of pulmonary circulation. Hypothesis: We hypothesized that pressure-flow relationships of the pulmonary circulation (mPAP/CO) would be associated with 6MWD in connective tissue disease (CTD). Methods: We prospectively performed 6-minute walk test and echocardiographic studies in 202 CTD patients (56±14 years; 11% male) with measurements of cardiac output using electric cardiometry. We have calculated the pulmonary artery pressure-cardiac output relationships as mPAP divided by CO (mPAP/CO). Results: Firstly, we have checked the accuracy of CO by electric cardiometry. In our cohort with invasive data, there is a good correlation between right heart catheter and electric cardiometry values of cardiac output (r=0.85; p &lt;0.001) with electric cardiometry measurements slightly underestimating cardiac output (bias -14% of the mean). Correlates of 6MWD were age (partial R= -0.19, p=0.009), early-diastolic mitral annular motion velocity (e’, partial R= 0.20, p=0.005), E/e’ (partial r= -0.16, p=0.028) and CO (partial r= 0.21, p=0.019) in the univariate analysis. In multivariate analysis, the mPAP/CO was strongly associated with 6MWD (t= -2.06, p= 0.042). Male gender and early-diastolic tricuspid annular motion velocity were also associated with 6MWD (t= 2.09, p=0.038 and t =2.92, p =0.004, respectively). Conclusions: Elevated mPAP/CO was associated with reduced 6MWD independent from LV and RV diastolic function. These results may recommend that we would assess not only the pressure but also the pressure-flow relationships of the pulmonary circulation in high risk group of PH.
Abstract 12616: Interactive Protein Network of Factor XIII In Platelet Lipid Rafts
Authors: Vahideh Rabani, Damien Montange, Nicolas F Meneveau, Siamak Davani
Journal: Circulation (2015)

Background: Factor XIII plays a pivotal role in platelet aggregation. Factor XIII depends on lipid rafts to assemble the proteins required for clot retraction. Several proteins in this assembly remain unidentified. The aim of this study was to investigate which proteins localized in platelet lipid rafts are related to Factor XIII. Methods: Lipid rafts of platelets were isolated by using Lubrol WX 0.05% (w/v) and sucrose gradient. After ultracentrifugation, sucrose fractions were sampled. Lipidomic analysis was performed to identify the platelet lipid raft fractions enriched in cholesterol (Ch) and sphingomyelin (SM) and less so in phosphatidylcholine (PC). These fractions were selected for further proteomic analyses. The network of associated proteins was drawn by STRING database. Results: Sucrose fractions containing platelet lipid rafts were identified (Figure 1A). After proteomics analysis, an interactive network of proteins around FXIIIA was observed (Figure 1B). For these 19 proteins, their STRING score (range 0.576 to 0.900) and the type of their interaction with FXIIIA (activation, binding, catalysis and reaction) are summarized in Table 1. Conclusion: We identified 19 associated proteins with Factor XIII in human platelet lipid rafts. This could provide further insights into clinical targets of pathways through this molecule.
Abstract 15641: Quantification of Left Ventricular Shape Differentiates Pediatric Pulmonary Hypertension Patients From Matched Controls
Authors: Jennifer L Wagner, Bruce F Landeck, Kendall Hunter
Journal: Circulation (2015)

Background: Changes in left ventricular (LV) shape are observed in patients with pulmonary hypertension (PH). Quantification of shape changes could serve as an additional tool to non-invasively monitor pediatric patients with PH. Decomposing the shape of a ventricle into a series of components and magnitudes will facilitate differentiation of healthy and PH subjects. Methods: Parasternal short axis echo images acquired from 42 pediatric subjects with PH as well as 42 age and sex matched normal control subjects underwent speckle tracking using Velocity Vector Imaging (Siemens) to produce series of x,y coordinates tracing the LV endocardium in each frame. A Fourier transform was then used to derive shape components and magnitudes from LV shape in each frame. Magnitudes from the first 11 components were normalized to heart size (magnitude/LV length as measured on apical view) and analyzed across a single cardiac cycle. Results: Fourier decomposition produced a series of shape components from short axis echo views of the LV (Figure 1). All 11 components analyzed were significantly different between groups (Figure 2). Conclusion: Quantification of LV shape can differentiate normal pediatric subjects from those with PH. Shape analysis is a promising new method to precisely describe shape changes observed in PH. Differences between groups speak to intra ventricular coupling that occurs in right ventricular overload and may describe phenomena such as mechanical hinge points at the septal-wall interface, myocardial discontinuities or deformations from reflected pressure waves. Further analysis surrounding timing and correlation to clinical parameters is underway.
Abstract 16038: Heterozygous Endothelin Receptor Type B Knockout Confers Cardiac Resistance to Extreme Hypoxia in Mice
Authors: Tsering Stobdan, Dan Zhou, Eilleen Ao-Ieong, Daniel Ortiz, Roy Ronen, Vineet Bafna, Pedro Cabrales, Gabriel G Haddad
Journal: Circulation (2015)

Rationale: To better understand human adaptation to hypoxia, we took advantage of one of the nature’s experiments at high altitude (HA) and studied Ethiopians, a human population that is well adapted to HA hypoxia. Using whole genome sequencing, we identified EDNRB, endothelin receptor type B, as a candidate gene involved in HA adaptation. Objective: We hypothesize that EDNRB plays a critical role in hypoxia and therefore in HA adaptation through regulating cardiac function. Methods and Results: We generated EdnrB knockout mice and found that the EdnrB-/+ mice were phenotypically normal. However, when treated with lower levels of oxygen (O2), EdnrB-/+ mice tolerated various levels of hypoxia, sustaining ejection fraction, cardiac contractility and cardiac output to even 5% O2. Blood lactate levels remained low and O2 delivery to vital organs was significantly higher in EdnrB-/+. Tissues sensitive to hypoxia, such as brain, heart and kidney, were less hypoxic indicating better peripheral perfusion. Conclusion: These data indicate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Our findings in EdnrB-/+ mice provide strong evidence that 1) EDNRB plays a key role in the adaptation to HA whereby a lower activation of EDNRB leads to a better cardiac performance under hypoxic conditions and 2) HA adaptation studies can be pertinent to understanding responses to acute hypoxia at sea level.
Abstract 11554: Chronic Cenderitide Administration Improves Cardiorenal Function and Remodeling in Experimental Heart Failure
Authors: Tomoko Ichiki, Gail J Harty, Brenda K Huntley, S Jeson Sangaralingham, Gerald E Harders, John C Burnett
Journal: Circulation (2015)

Introduction: Heart failure (HF) is a major health burden in which renal impairment worsens prognosis. Targeting the vicious cycle between heart and kidney may be a more optimal therapeutic strategy for HF. The cardiac natriuretic peptides have cardiorenal protective effects through their receptor GC-A and GC-B. We sought to determine the actions of chronic administration of the dual GC-A/GC-B agonist cenderitide (CD-NP) upon cardiorenal function in experimental HF. Hypothesis: Chronic cenderitide therapy will improve cardiorenal function in HF. Methods: Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days which mimics advanced overt HF in humans. Canines (n=5 of each group) were treated with or without cenderitide (Capricor Therapeutics) subcutaneous injection (SQ) twice per day (SQ-BID, 10 ug/kg/day), cenderitide continuous SQ pump (SQ-pump, 5 ng/kg/min), or oral enalapril (ACEi, 0.5 mg/kg/day) for 10 days from the beginning of pacing. We defined hemodynamics, echo parameters, circulating neurohumoral factors at day 11, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, and inflammation in left atrium which undergoes early remodeling in this model. Results: The SQ-pump group showed significantly less atrial and renal weights, higher cardiac output, glomerular filtration rate, and % ejection fraction, and lower systemic vascular resistance and plasma renin activity (all p&lt;0.05) without lowering mean arterial pressure (MAP), whereas SQ-BID and ACEi lacked these effects together with lowering MAP compared to untreated canines. Gene profile analyses showed gene related to inflammatory cytokines such as TNF-alpha, IL-1 beta, and ROCK-2, and apoptosis such as caspase 7, Fas ligand, C-Myc and TP53 were suppressed (all p&lt;0.05) in SQ-pump but not SQ-BID or ACEi compare to un-treated group. Conclusions: Continuous SQ administration of cenderitide demonstrated superior beneficial effects on cardiorenal function and remodeling together with inhibition of circulating renin and tissue inflammatory and apoptosis pathways. Our studies suggest that continuous administration of cenderitide may provide cardiorenal protection in the setting of advanced HF.
Abstract 14043: Enhanced Integrin α4β1-mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes
Authors: Timothy O'Toole, Wesley Abplanalp, Daniel Conklin, Joe Cantor, Mark Ginsberg, Aruni Bhatnagar
Journal: Circulation (2015)

While previous studies have identified a deficit of circulating endothelial progenitor cells (EPCs) in diabetic conditions (diabetic “mobilopathy”), the basis for these deficits are not completely understood. To model the adhesive properties of EPCs in diabetic conditions, we cultured these cells in high glucose and found that they had stronger adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1β (PRKAR1β), consequent activation of protein kinase A (PKA), and phosphorylation of the α4 integrin on serine 988. The potentiating effects of high glucose on adhesion were mimicked by direct PKA activation and reversed by treatment with a PKA inhibitor, overexpression of PRKAR1β or expression of a phosphorylation-defective α4 integrin (α4-S988A). Using the STZ model of type I diabetes, we show that α4-S988A-expressing mice have more circulating EPCs than do their wild type counterparts (2.6 ± 0.5 fold). Furthermore, the diabetic α4-S988A mice demonstrate enhanced revascularization (1.50 ± 0.3 fold vs. WT) and tissue repair after hind limb ischemia. Thus, hyperglycemic conditions potentiate the adhesion of EPCs to bone marrow stromal cells which results in an in vivo mobilization defect. Mutational reversal of this increased adhesion liberates EPCs and promotes re-endothelialization in ischemic tissues, suggesting a potential therapeutic target to treat diabetic vascular complications.
Abstract 10386: Clinical and Genetic Risk Factors for Post-Operative Atrial Tachycardia After Congenital Heart Surgery in Infants
Authors: Amy M O'Connor, Kim Crum, Andrew H Smith, Prince J Kannankeril
Journal: Circulation (2015)

Introduction: Atrial tachycardia (AT) after infant congenital heart disease (CHD) surgery has been associated with increased mortality. Common genetic variants in PITX2 (rs2200733) and IL6 (rs1800795) have been associated with post-operative AT in adults, but have not been studied in infants after CHD surgery. Hypothesis: Genetic variants in PITX2 and IL6 are associated with post-operative AT in infants with CHD. Methods: Children less than 1 year of age undergoing their first CHD surgery at our center between 9/2007 and 3/2014 who consented to the study were included. Subjects provided a DNA sample and had repeated daily assessment of telemetry with documentation of all arrhythmias and clinical variables. Genotyping was performed in the Vanderbilt genomics core lab using the TaqMan PCR Core Reagent Kit. Children with and without AT were compared using chi-square or unpaired t-test as appropriate. Results: Of 923 enrolled infants, 141 had post-operative AT (15.3%), 79 of who required treatment (8.6%). AT was associated with increased mortality (12.1% mortality with AT; vs. 5.5% no AT, P = 0.004), longer hospital stay (mean of 49 days with AT; vs. 23 days no AT, P &lt; 0.0001), intensive care unit (ICU) stay (mean of 34 days with AT; vs.13 days no AT, P &lt; 0.0001), and mechanical ventilation duration (mean of 22 days with AT; vs. 8 days no AT, P &lt; 0.0001). Age, epinephrine use, milrinone use, bypass time, cross-clamp time, lactate, and number of pump runs were associated with AT and AT requiring treatment. PITX2 and IL6 genotypes were not significantly associated with AT or AT requiring treatment. Conclusions: AT is associated with increased mortality and longer hospital stay, ICU stay, and mechanical ventilation duration. Numerous operative factors contribute to AT after infant CHD surgery. PITX2 and IL6 genetic variants were not found to be significantly associated with post-operative AT in infants undergoing CHD surgery in our study.
Abstract 12229: MicroRNA Regulation of JAK-STAT System in the Atrial Fibrillation-Related Fibrotic Response
Authors: Yu Chen, Sirirat Surinkaew, Jiening Xiao, Chia- T Wu, Hai Huang, Yiguo Sun, Dobromir Dobrev, Stanley Nattel
Journal: Circulation (2015)

Introduction: MicroRNAs (miRNAs) are involved in cardiac remodeling, but their role in atrial fibrillation (AF) is poorly understood. JAK-STAT signalling is activated by the pro-fibrotic mediator PDGF, but its contribution to AF substrate formation is unknown. Here, we investigated miRNA regulation of the JAK-STAT system in in the heart failure (HF) induced AF fibrotic substrate. Methods: HF was induced in dogs by ventricular tachypacing (VTP, 240 bpm) for 2 weeks. Fibroblasts (FBs) isolated from the left atrium (LA) and left ventricle (LV) of control (CTL) dogs were treated with PDGF-AB. PDGF, JAK2, STAT3 and miRNA expression was assessed by qPCR. JAK2, STAT3 and collagen-I (COL-1) proteins were quantified by Western Blot. miRNA targets were validated by luciferase reporter assay. miRNA mimic or antisense oligonucleotides (AMOs) were used for miRNA manipulation in FBs. Results: HF dogs developed AF susceptibility and LA-selective fibrosis beginning at 1 wk VTP. PDGF and JAK2 mRNA, along with phosphorylated (activated) JAK2 protein, were increased in HF atria (by 1.4-2.9* fold, *p&lt;0.05). miR-30a and miR-133a were predicted bioinformatically to target JAK2, and were downregulated by 51%-52%** and 48%-71%** (**p&lt;0.01) in HF LA FBs at 1-2 wk VTP. PDGF-AB increased the expression of JAK2 and STAT3 mRNA (by 1.4-1.5* fold) and COL-1 protein (by 2*** fold, ***p&lt;0.001) in canine LA FBs, while reducing the expression of miR-30a and miR-133a (by ~50%-80% ***). Smaller changes were seen in LV FBs with PDGF-stimulation. Luciferase assay confirmed miR-30a and miR-133a targeting of JAK2. Overexpression of miR-133a downregulated JAK2 mRNA (by 30%***) and protein (by 50%, p=0.05) in LA FBs. This effect was abolished by co-transfection of miR-133a and AMO-133a. The upregulation of JAK2 and COL-1 expression induced by PDGF-AB stimulation was reversed by miR-133a overexpression in LA FBs (reduced by 49%* and 53%*** versus PDGF stimulation alone). Conclusions: PDGF-induced disinhibition of JAK2 expression by downregulation of miR-30a and miR-133a may contribute to AF-associated fibrotic responses. MicroRNA targeting of the JAK-STAT system regulates LA FB function, appears to be involved in HF-induced LA fibrosis and is a potential therapeutic target for AF prevention.
Abstract 12435: Mitochondrial Calcium Flux Modulates Pacemaker Activity in Embryonic Stem Cell-Derived Cardiomyocytes
Authors: An Xie, Anyu Zhou, Hong Liu, Guangbin Shi, Kenneth R Boheler, Samuel C Dudley
Journal: Circulation (2015)

Introduction: Ca2+ release from the sarcoplasmic reticulum (SR) is known to contribute to spontaneous activity via the cytoplasmic Na+-Ca2+ exchanger (NCX). Mitochondria are known to participate in Ca2+ cycling. We studied the role of mitochondrial Ca2+ flux in spontaneously activity of embryonic stem cells (ESC)-derived CMs. Methods: CMs were derived from wild type (Wt) and ryanodine receptor type 2 knockout (RYR2-/-) mouse ESCs and differentiated for 19-21 days. Action potentials (APs) were recorded by perforated whole cell current-clamp. Cytoplasmic Ca2+ transients were determined by fluorescent imaging. Mitochondrial Ca2+ transients were monitored simultaneously with APs. Results: While If blocker, 10μM ivabradine, had no significant effect on the automaticity, SR Ca2+ handling inhibitors, 10 μM ryanodine and 2 μM 2-APB, reduced the spontaneous beating rate to 56% and 73% respectively in Wt CMs. Inhibition of mitochondrial Ca2+ flux by 10 μM Ru360 showed a similar inhibitory effect on the pacemaker activity.To isolate the contribution of mitochondrial Ca2+, we used RYR2-/- CMs. In RYR2-/- CMs, beating rate was dependent on SR Ca2+ uptake and release from IP3 and the Na+/Ca2+ exchange current but was independent of sarcolemmal Ca2+ influx through L-type Ca2+ channels. In these cells, MCU inhibition by pharmacological or molecular biological means reduced beating rate. Depolarizing mitochondria prevented spontaneous beating. The mitochondrial NCX blocker, 1 or 3μM CGP-37157, terminated AP firings. Conclusions: Mitochondrial Ca2+ cycling plays a role in spontaneous beating activity in embryonic stem (ES) cell-derived cardiomyocytes. Mitochondrial dysfunction may contribute to altered pacemaker activity in cardiomyopathy.